Identification of common variants influencing risk of the three-repeat tauopathy Pick’s disease: a genome wide association study
Year: 2025
Type: preprint
Study design: Observational Study
Abstract: Pick’s disease (PiD) is a rare cause of sporadic frontotemporal dementia, neuropathologically defined by the presence of Pick bodies consisting of aggregates of 3-repeat tau. Given the genetic aetiology of PiD remains unresolved, we assembled the Pick’s disease International Consortium (PIC) to identify susceptibility loci through a genome-wide association study (GWAS). A GWAS was conducted in 294 autopsy confirmed PiD cases and 1,055 controls. Lead variants were annotated using the Functional Mapping and Annotation of GWAS (FUMA) platform, followed by co-localisation analyses using the METABRAIN dataset and statistical finemapping using FINEMAP and SuSiE. After exclusion of 3 cases of MAPT mutations, no variants were associated with risk of PiD at genome-wide significance ( p < 5 × 10 -8 ). The strongest association was on chromosome 4 (4p13, lead SNP rs112161979, OR = 7.53, 95% Confidence Interval (CI) = 3.62-15.65, p = 6.37 × 10 -8 ) followed by chromosome 11 (11p15.4, lead SNP rs66481907, OR = 2.10, 95% CI = 1.54-2.84, p = 1.83 × 10 -6 ). rs112161979 is an intronic SNP in the KCDT8 gene, encoding a potassium channel tetramerization domain that acts as an auxiliary subunit for GABA B receptors, whilst rs66481907 is an intronic SNP in TRIM22 , encoding an E3 ubiquitin-protein ligase. Our GWAS provides the first evidence of possible genetic risk for PiD that implicate the modulation of GABA B receptor signalling and inflammation, in disease pathogenesis. Replication of these findings will be important, but our results suggest that, if present, the genetic risk of PiD beyond MAPT mutations is low.
Source: medRxiv
Authors: William J Scotton, Rebecca R Valentino, Alejandro Martinez-Carrasco, Raquel Real, Hannah L Macpherson, Nicole Tamvaka, Kin Mok, Michael G Heckman, Christopher Kobylecki, Valentina Escott-Price, James B Rowe, Huw R Morris, Rosa Rademakers, Shanu F Roemer, Tammaryn Lashley, Dennis W Dickson, Jonathan D Rohrer, John A Hardy, Owen A Ross, Maryam Shoai
Institutions: UCL Queen Square Institute of Neurology, University College London, Mayo Clinic, Mayo Clinic in Florida, Hong Kong University of Science and Technology, UK Dementia Research Institute, University of Manchester, Cardiff University, MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Medical Research Council, University of Antwerp, VIB-UAntwerp Center for Molecular Neurology
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Impact of coding and non-coding variation in progressive supranuclear palsy, Understanding the role of MAPT in Parkinsonian disorders, Einstein Aging Study, Identifying genes and Pathways that impact Tau Toxicity in FTD, Synergistic Interaction of amyloid-beta and alpha-synuclein in Lewy body Dementia, Genetics and Molecular Biology of Parkinsonism, Mayo Alzheimer's Disease Research Center
OpenAlex ID: W7117374427